PROJECT SUMMARY Chronic kidney disease (CKD) affects 20 million people in the United States. Family members of patients with CKD, particularly diabetic kidney disease, are at increased risk of developing CKD themselves. However, genetic studies cannot yet account for this apparent heritability; neither can known environmental risk factors, such as diabetes or hypertension. Our proposal is aimed at investigating whether the interaction between the environment and the DNA can account for this heritability. Environmental factors, such as diabetes, are known to affect DNA control mechanisms, called epigenetics. The epigenome controls whether DNA is active or inactive by making changes to the DNA that do not change the nucleotide sequence itself. These changes in turn lead to changes in the level of gene expression. Our study will investigate this mechanism on a genome wide level in human kidney tissue. We will examine both genome wide changes to the epigenome, specifically cytosine methylation, and gene expression levels in human kidney samples. We will compare human kidney samples with diabetic kidney disease to control samples, both with and without diabetes, in order to identify epigenetic changes that may cause disease development. We will compare samples with diabetic kidney disease to samples with hypertensive kidney disease in order to distinguish the effects of these environmental phenotypes. In addition, we will analyze changes to the epigenome, which are associated with rapid progression to kidney failure. We will analyze the genomic locations of these changes in order to identify novel pathways involved in CKD development and progression. These pathways may represent therapeutic targets for the prevention of kidney failure.